What is the role of chemotherapy after surgery in the treatment of operable stage I NSCLC?

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What is the role of chemotherapy after surgery in the treatment of operable stage I NSCLC?

Post-operative adjuvant chemotherapy for stage IA

Trials of adjuvant chemotherapy in the form of the tablet Tegafur- Uracil have demonstrated a survival benefit, but these trials have involved Japanese patients only and the benefit has not been demonstrated for tumours less than 2 cm in size. Meta-analyses support this finding. One study, also from Japan, demonstrated a benefit with bestatin, an aminopeptoidase inhibitor specifically for stage I NSCLC of squamous cell histology.[1] Chemotherapy has not been demonstrated to provide a benefit in this subgroup. In many studies, patients with stage IA are excluded. When included, stage IA patients usually represent a small percentage of the total patient numbers unless the study is specifically designed for stage I NSCLC only. Burdett et al have performed an individual patient data meta-analysis as part of a Cochrane Review. 414 patients with stage IA disease were included in this analysis from trials that evaluated platinum based adjuvant chemotherapy. 1644 stage IA patients came from studies that evaluated UFT/Tegafur. This meta-analysis could not demonstrate a convincing survival benefit for adjuvant chemotherapy when used as part of the treatment of stage 1A NSCLC. [2]

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Post-operative adjuvant chemotherapy for stage IB

As above, several trials from Japan have demonstrated a benefit for Tegafur- Uracil,[3][4] and another study from Japan showed a benefit with bestatin.[1] The role of chemotherapy, particularly platinum based combination chemotherapy, remains contentious in this setting. Pooled analyses of studies that investigated adjuvant chemotherapy using non-platinum based regimens, particularly alkylating agents, showed that patients treated with chemotherapy had worse survival. Adjuvant therapy utilizing platinum based chemotherapy combinations, however, has been associated with a survival advantage in the stage IB disease subgroup. Individual studies have produced variable results, but most of these have been inadequately powered to detect a survival advantage, accepting the better prognosis of this group and the small absolute benefit observed in several meta-analyses. An individual patient data meta-analysis as part of a Cochrane Review did demonstrate a survival benefit for adjuvant chemotherapy after surgery for stage 1B NSCLC, with an estimate of the absolute benefit measuring 5%. [2]. This analysis included data from 3005 patients, the majority include in trials that evaluated platinum based chemotherapy regimens as adjuvant therapy. The CALGB 9633 study specifically investigated stage IB NSCLC, and a survival benefit was not demonstrable. The study, however, was powered to detect a survival difference of 13% so smaller difference may have been missed. A subgroup analysis did suggest a benefit for patients with tumours that were greater than 4 cm in maximal diameter.[5] A retrospective analysis from the National Cancer Database in the USA revealed a low utilisation of adjuvant chemotherapy in stage I NSCLC, but those that received adjuvant chemotherapy had a better survival. The survival benefit was also demonstrable in patients with tumours that were less than 4 cm in size, [6]

Two of the largest phase III trials that demonstrated a survival benefit used cisplatin combined with vinorelbine (JBR.10 (cisplatin + vinorelbine only) and ANITA (cisplatin + vinorelbine in 90% of patients). 45% of the patients from JBR.10 had stage IB disease and the remainder were stage II. The effect of chemotherapy appeared larger in patients with stage II disease, but the test for interaction was not significant and so the authors were reluctant to deduce that the effect of adjuvant chemotherapy is not seen in stage IB.[7] Longer term follow-up data from JBR.10 did reveal that there was a trend for interaction, suggesting that stage IB patients did not benefit.[8] A cost efficacy analysis from JBR.10 demonstrated that the cost of the benefit obtained was comparable to other accepted medical interventions. Compliance has also been shown to be high.[9] A Quality of Life analysis from JBR.10 did reveal maintenance of QoL for the majority of patients on adjuvant chemotherapy.[10] In the ANITA trial, 36% (301) of the patients had stage I. There was an absolute survival benefit of 8.6% at five years in the chemotherapy arm for all stages. The test for interaction between tumour stage and chemotherapy on survival was not significant (p=0.07), indicating that the benefit associated with adjuvant chemotherapy did not differ in patients with stage IB NSCLC. [11]

Long-term data from the International Adjuvant Lung Cancer Trial (IALT) revealed that adjuvant chemotherapy reduced the risk of local cancer recurrence and non-brain metastases, but it id not reduce the rate of brain metastases. Whilst cancer recurrence and cancer related death was reduced, there was an observed increase in non-cancer related deaths seen after 5 years of follow up. The authors postulated that the deaths may be attributable to the late effects of cisplatin, but the observed benefit of adjuvant chemotherapy in related to reducing cancer deaths outweighed the numerically low non-cancer deaths ([12])

The largest and most contemporary meta-analysis has demonstrated a 5% survival benefit in favour of adjuvant chemotherapy for the treatment of stage IB disease [2]. This meta-analysis included individual patient data form all the eligible trials that compared chemotherapy versus no chemotherapy. Another meta-analysis, this type using summary statistics from the included trials and not IPD, examined stage IB NSCLC only and included 4656 patients from 16 eligible trials. This also reported a survival benefit with adjuvant chemotherapy, but the benefit was restricted to those that received more than 4 cycles of cisplatin based chemotherapy or Tegafur [13] A meta-analysis using individual patient data from four of the largest RCTs showed a benefit, but subgroup analysis suggested the benefit was restricted to stage II and III.[14] The largest of the randomized controlled trials was the International Adjuvant Lung Cancer Trial, which included 681 patients with stage I disease. A survival benefit for chemotherapy with cisplatin containing regimens was seen. This benefit was not influenced by stage.[15] A small randomized phase II study from Italy did support a benefit in stage IB disease using cisplatin and etoposide.[16] An EORTC study showed no benefit for stage I-III NSCLC with adjuvant MVP – mitomycin, vinblastine and cisplatin.[17] Several meta-analyses and systematic reviews have demonstrated a survival benefit for stage IB disease, but of a small magnitude (less than 5%, usually 2-3%).

The Cochrane meta-analysis addressed the question of the role of combined chemotherapy and radiotherapy given in the adjuvant setting. Twelve trials were included that compared adjuvant chemo-radiation versus adjuvant irradiation alone. In 9 studies the chemotherapy was given before the radiotherapy and in 4 studies the chemotherapy and the radiotherapy were administered concurrently (for 1 study both pre RT chemotherapy and concurrent CRT was administered). A total of 2660 patients were included. For cisplatin-based combination chemotherapy there was a benefit of 4% in absolute survival at five years, increasing from 29 to 33% (p=0.009). [2]


Evidence summary and recommendations

Evidence summary Level References
In studies of adjuvant chemotherapy for stage I NSCLC, stage IA patients were either excluded or represent a small percentage of the total number of included patients. There is no evidence of a clear survival benefit for post-operative adjuvant chemotherapy for stage IA disease.

Last reviewed December 2015

I [1], [3], [18], [5], [7], [8], [9], [10], [11], [15], [16], [17], [2]
Evidence-based recommendationQuestion mark transparent.png Grade
Post-operative adjuvant chemotherapy is not recommended for stage IA NSCLC.

Last reviewed December 2015

B


Evidence summary Level References
Platinum-based adjuvant chemotherapy for patients with stage IB NSCLC is associated with a survival benefit. Meta-analyses reveal an absolute survival benefit of 5%. The benefit is observed in tumours that are greater than 3-4 cm in maximal diameter.

Last reviewed December 2015

I [1], [3], [18], [5], [7], [8], [9], [10], [11], [15], [16], [17], [2], [12], [13], [6]
Evidence-based recommendationQuestion mark transparent.png Grade
Platinum-based adjuvant chemotherapy is recommended for all patients with stage IB NSCLC.

Last reviewed December 2015

B


References

  1. 1.0 1.1 1.2 1.3 Ichinose Y, Genka K, Koike T, Kato H, Watanabe Y, Mori T, et al. Randomized double-blind placebo-controlled trial of bestatin in patients with resected stage I squamous-cell lung carcinoma. J Natl Cancer Inst 2003 Apr 16;95(8):605-10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12697853.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Burdett S, Pignon JP, Tierney J, Tribodet H, Stewart L, Le Pechoux C, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev 2015 Mar 2;3:CD011430 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25730344.
  3. 3.0 3.1 3.2 Ueda H, Sakada T, Kuwahara M, Motohiro A. A small randomized phase III single-center trial on postoperative UFT administration in patients with completely resected non-small cell lung cancer. Anticancer Drugs 2004 Jan;15(1):29-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15090740.
  4. Nakagawa M, Tanaka F, Tsubota N, Ohta M, Takao M, Wada H, et al. A randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I non-small-cell lung cancer: the West Japan Study Group for Lung Cancer Surgery (WJSG)--the 4th study. Ann Oncol 2005 Jan;16(1):75-80 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15598942.
  5. 5.0 5.1 5.2 Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008 Nov 1;26(31):5043-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18809614.
  6. 6.0 6.1 Speicher PJ, Gu L, Wang X, Hartwig MG, D'Amico TA, Berry MF. Adjuvant Chemotherapy After Lobectomy for T1-2N0 Non-Small Cell Lung Cancer: Are the Guidelines Supported? J Natl Compr Canc Netw 2015 Jun;13(6):755-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26085391.
  7. 7.0 7.1 7.2 Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005 Jun 23;352(25):2589-97 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15972865.
  8. 8.0 8.1 8.2 Butts CA, Ding K, Seymour L, Twumasi-Ankrah P, Graham B, Gandara D, et al. Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. J Clin Oncol 2010 Jan 1;28(1):29-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19933915.
  9. 9.0 9.1 9.2 Alam N, Shepherd FA, Winton T, Graham B, Johnson D, Livingston R, et al. Compliance with post-operative adjuvant chemotherapy in non-small cell lung cancer. An analysis of National Cancer Institute of Canada and intergroup trial JBR.10 and a review of the literature. Lung Cancer 2005 Mar;47(3):385-94 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15713522.
  10. 10.0 10.1 10.2 Bezjak A, Lee CW, Ding K, Brundage M, Winton T, Graham B, et al. Quality-of-life outcomes for adjuvant chemotherapy in early-stage non-small-cell lung cancer: results from a randomized trial, JBR.10. J Clin Oncol 2008 Nov 1;26(31):5052-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18809617.
  11. 11.0 11.1 11.2 Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association (ANITA)): a randomised controlled trial. Lancet Oncol 2006 Sep;7(9):719-27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16945766.
  12. 12.0 12.1 Rotolo F, Dunant A, Le Chevalier T, Pignon JP, Arriagada R, IALT Collaborative Group. Adjuvant cisplatin-based chemotherapy in nonsmall-cell lung cancer: new insights into the effect on failure type via a multistate approach. Ann Oncol 2014 Nov;25(11):2162-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25193990.
  13. 13.0 13.1 He J, Shen J, Yang C, Jiang L, Liang W, Shi X, et al. Adjuvant Chemotherapy for the Completely Resected Stage IB Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 2015 Jun;94(22):e903 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26039122.
  14. Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008 Jul 20;26(21):3552-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18506026.
  15. 15.0 15.1 15.2 Arriagada R, Dunant A, Pignon JP, Bergman B, Chabowski M, Grunenwald D, et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 2010 Jan 1;28(1):35-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19933916.
  16. 16.0 16.1 16.2 Roselli M, Mariotti S, Ferroni P, Laudisi A, Mineo D, Pompeo E, et al. Postsurgical chemotherapy in stage IB nonsmall cell lung cancer: Long-term survival in a randomized study. Int J Cancer 2006 Aug 15;119(4):955-60 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16550600.
  17. 17.0 17.1 17.2 Scagliotti GV, Fossati R, Torri V, Crinò L, Giaccone G, Silvano G, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 2003 Oct 1;95(19):1453-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14519751.
  18. 18.0 18.1 Nakagawa M, Tanaka F, Tsubota N, Ohta M, Takao M, Wada H, et al. A randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I non-small-cell lung cancer: the West Japan Study Group for Lung Cancer Surgery (WJSG)--the 4th study. Ann Oncol 2005 Jan;16(1):75-80 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15598942.

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Appendices

Further resources

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